Pharmacological characterization of PD 152255, a novel dimeric benzimidazole dopamine D3 antagonist.
152255 (E-1,1'-(2-butene-1,4-diyl)bis[2-[4-[3-(1-piperidinyl)propoxy]-phe nyl]-1H-benzimidazole]) exhibited high affinity (Ki = 12.7 nM) for human dopamine (DA) D3 receptors expressed in CHO K1 cells but not for DA D2L receptors (Ki = 565 nM), DA D42 or DA D1 receptors (Ki > 3 microM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D3 receptors was demonstrated by blockade of quinpirole-stimulated [3H]-thymidine uptake in D3 transfected cells, an effect that was 28-fold more potent than in D2-transfected cells. Unlike classical DA D2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D3 antagonist that may have antipsychotic activity.
Corbin
A E
AE
Psychiatric Disorders Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Pugsley
T A
TA
Akunne
H C
HC
Whetzel
S Z
SZ
Zoski
K T
KT
Georgic
L M
LM
Nelson
C B
CB
Wright
J L
JL
Wise
L D
LD
Heffner
T G
TG
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000096:biosynthesis; D001923:Brain Chemistry / Q000187:drug effects; D016466:CHO Cells; D018680:Cholinergic Antagonists / Q000494:pharmacology; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3; D015398:Signal Transduction / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism
C111108:1,1'-(2-butene-1,4-diyl)bis(2-(4-(3-(1-piperidinyl)propoxy)phenyl)-1H-bnzimidazole); D014150:Antipsychotic Agents; D001562:Benzimidazoles; D015306:Biogenic Monoamines; D018680:Cholinergic Antagonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493594:Drd3 protein, mouse; C493595:Drd3 protein, rat; D010880:Piperidines; D050637:Receptors, Dopamine D3; D013936:Thymidine